Non‐viral strategies of intra‐ocular gene delivery

Abstract

Abstract Purpose Systemic anti TNF strategies are efficient to treat intraocular inflammation but require repeated injections and are associated to severe systemic side effects. Our aim was to develop a non viral gene transfer method to produce locally anti‐inflammatory proteins in a sustained and minimally invasive manner in the ocular media. For this purpose, we have transformed the ciliary muscle into a bioreactor, using an electrically assisted gene transfer technique. Methods Electrotransfer (ET) of plasmids, encoding for different variants of TNF alpha soluble receptors, was performed in the ciliary muscle cells. Using toptimized conditions, soluble receptors were dosed in the ocular media up to 8 months after a single treatment. The technique has been applied in two models of intraocular inflammation: Endotoxin‐Induced Uveitis (EIU) and auto immune experimental uveitis (EAU) in rats. Results When performed 8 days or 3 months before the LPS challenge, ET significantly reduced both clinical and histological signs of EIU. Particularly, iNOS, IL6 and TNF were down regulated while IL10 was upregulated. Importantly, systemic TNF alpha was not decreased demonstrating a local effect of the treatment. In EAU, ET significantly delayed the onset of EAU and deceased its severity. Similarly, a switch towards a Th2 cytokines profile was observed in the ocular media without any effect on systemic TNF alpha. Conclusion ‐ ET is a safe and efficient non viral method to produce locally TNF alpha soluble receptors. ‐ Local anti TNF allows for a local intraocular immunomodulation, without affecting systemic TNF. ET could therefore be used to reduce systemic side effects of anti TNF and prevent repeated injections.